Skin Cancer Chemoprevention by Silibinin: Mechanisms and Efficacy

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Project Summary Abstract The most important risk factor for basal cell carcinoma (BCC), accounting for ~4 million new cases each year, is solar ultraviolet B radiation (UVB) exposure. One of the key molecular features of BCC is sustained activation of hedgehog (Hh) pathway through inactivating mutations in tumor suppressor gene Ptch or activating mutations in Smoothened (SMO). Consequently, extensive efforts have been made to target activated Hh pathway to treat BCC, though with toxic side effects and drug resistance. Due to these limitations, recent studies have also focused on chemopreventive strategies to manage BCC. In specific Aim I of the parent grant, we proposed to determine the preventive efficacy of topical application of silibinin on a) chronic UVB-induced macroscopic BCC formation as well as b) on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs. Notably, the outcomes from these studies (in the parent grant) have shown that topical silibinin application has significant protective effects against BCC growth and progression (pl. refer to efficacy outcomes section, B5: Fig 1-4). Given these important findings in our completed studies in the parent grant and the fact that silibinin has also shown strong chemopreventive and anti-cancer potential when given orally (by gavage and/or dietary feeding) in other cancers [including skin squamous cell carcinoma (SCC)], there is a compelling likelihood that silibinin would also prevent BCC progression when given orally. Such studies were not proposed in the parent grant, but (based on our completed studies) merit detailed investigation and forms the basis of this supplement; we expect similar protective effects using oral silibinin dosing in our proposed studies. Also, the anticipated efficacy of orally administered silibinin against BCC progression from ‘micro’ to ‘macro’ grade will highlight the tremendous potential of silibinin for its preventive and interventive applications against BCC progression. Our aims are: I) to determine the preventive efficacy of oral feeding of silibinin on the progression of UVB-induced microscopic BCC lesions to more advanced forms of BCCs; and II) to determine potential biomarkers of BCC chemopreventive efficacy of silibinin; specifically, to identify silibinin-associated gene expression biomarkers and correlate them with the observed effects. Considering that silibinin has a long history of human use as a widely consumed dietary supplement around the world and is considered exceptionally safe, this supplement proposal is highly significant as successful results from proposed aims would have strong translational implications in the prevention and intervention of BCC.